20-amino-12, 18-cyclopregnane derivatives



United States Patent 20-AMINO-12,IS-CYCLGPREGNANE DERIVATIVES VlasiosGeorgian, Belmont, Mass, and James F. Kerwin,

Broomall, Pa., assignors to Smith Kline & French Laboratories,Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed July31, 1951, Ser. No. 127,825

12 Claims. ((11. 260-397.3)

FORMULA I in which:

E represents on or ,8, represents ,6 and i represents a.

R represents hydroxy or, when taken together with the ring methylenegroup to which it is attached, keto. R represents hydrogen or methyl;when a A vinylene moiety is present, of course, R is necessarily methyl.R represents hydrogen, fl-hydroxy or, when taken together With the ringmethylene group to which it is attached, keto.

R represents hydrogen or iluoro.

R represents hydrogen, methyl or fiuoro.

R represents hydrogen or methyl.

R and R are hydrogen or lower alkyl of from 1-4 carbons inclusive, atleast one of which is alkyl.

Preferably only one of R R and R is a substituent other than hydrogen.

Advantageous compounds are those of Formula I in which R, is keto, R Rand R are hydrogen, R is hydrogen and R is methyl.

The compounds represented by Formula I may be used in the form of theiracid addition salts. When used as therapeutic agents such salts must bepharmaceutically acceptable, such as the hydrochloride, sulfate,phosphate, etc. When used as intermediates, any acid addition orquaternary ammonium salt may be substituted. These addition compoundsare prepared by reacting the base with an acid or reactive alkyl halidein a suitable organic solvent, such as ether or benzene. Such additioncom pounds are considered part of this invention and fully equivalent tothe bases of Formula I. Also, 0 or N-acyl derivatives with a maximum of8 carbon atoms can be prepared if desired by standard acylationprocedures Well-known to the art, such as reaction with an acid chlorideOr anhydride. Such derivatives are also equivalent to the parentcompounds.

3,019,236 Patented Jan. 30, 1952 It will be recognized by one skilled inthe art that catalytic reduction conditions, such as those under whichthe ZO-amino function or the ll-hydroxy function are produced, give riseto mixtures of the a or {3 isomers which can be separated by fractionalcrystallization if desired. Practically speaking, the20a-aminol1B-hydroxy congeners are the most important members of theseries and are preferred. Where there is no designation of configurationin the examples, a mixture of 0c and 5 isomers is present. The condensedcyclopropyl ring is [3,}? in 1'elation to the steroid nucleus and is sorepresented in the disclosure of this invention.

It was unexpectedly found that when ll-keto-lS-halo steroids having thestructure:

FORMULA II in which R R R R R R and Y are as in Formula I and X ischloro or bromo, are heated under certain conditions to form conaninesas described in our copendingapplication, Serial No. 843,334 filedSeptember 30, :1959 and our US. Patent No. 2,983,736, a by-product wasalso obtained, which proved to be the 12,18-cyclopregnanes of Formula I.

The reaction conditions of the intramolecular condensation have beenfound to consist of reaction of the 18-halosteroids under strongly basicconditions in solvents in which th basic reagent and the steroidstarting material are substantially soluble. For instance, we have foundthat carbonates, such as potassium carbonate, are not sufliciently basicto yield appreciable amounts of the cyclic product but givepredominantly the conanine. The most advantageous method of carrying outthe reaction is to react the 18-halo starting material in alcoholicalkali metal hydroxide, ethoxide or methoxide solution at from roomtemperature up to the reflux temperature of the reaction solution.Preferred alkali metals are sodium or potassium. The alcoholic solutioncan be chosen from those usually used in organic chemistry, particularlyethanol, methanol or isopropanol. The reaction time has been found notto be critical and can vary from overnight at room temperature to a fewminutes in refluxing ethanol. Reaction conditions other than thosediscussed above have been found to be of little additional advantage.

The starting material compounds for th reaction can possess any of theamine functions as disclosed herebefore. Additionally, an O-acyl orN-acyl derivative, such as O or N-tritluoroacetyl compounds, can be usedif desired since the acyl moiety will be removed during the basiccondensation reaction. Also if desired forconvenience, an acid additionsalt of the ZO-aminosteioid may be used, such as the trifluoroacetatesalt.

The preparation of the IS-chlorosteroid starting material is disclosedin more detail in United States Patents,- No. 2,959,586, No. 2,975,174,No. 2,960,503 and especially No. 2,983,736 as well as in applications,Serial No. 1,450 filed January 11, 1960, Serial No. 843,334 filedSeptember 30, 1959 and Serial No.

9, 1961. Briefly, the l9 chloro compounds are prepared 88,034 filedFebruary from the known 20-keto compounds which are fully described inthe prior art by the following steps: reductive alkylation with aprimary lower alkylamine to form the 2l-alkylamine derivative,N-chlorination in chloroform or methylene chloride solution with sodiumhypochlorite solution to form the N-chloro derivatives, then ultravioletirradiation in trifluoroacetic acid solution to form the desiredl8-chlorosteroid. While many of the preliminary reactions for preparingnecessary starting materials are described in detail in the previouspatents or applications referred to, several model synthetic examplesare presented hereafter for complete clarity for those skilled in theart.

The ll-keto group of the starting materials represented by Formula II isessential to the course of the condensation reaction. The congenerswhich are part of this invention in which R is hydrogen or hydroxy areprepared by reduction of the ll-keto function by standard reactions. The12,18-cyclo moiety has been found to be very stable under many chemicalreactions standard in the steroid art, therefore, a wealth of obvioussubstituents in the steroid nucleus can be made by those skilled in theart other than those shown as illustrative in the following examples.

Example 1 Fifteen grams of 3a-hydroxypregnan-11,20-dione is dis solvedin 200 ml. of ethanol containing 15-20 g. of methylamine, and the clearsolution is allowed to stand for five hours. It is then shaken with 1.0g. of platinum oxide catalyst and hydrogen at an initial pressure of 50p.s.i. Hydrogenation commences after an induction period of one-half toone hour. When one mole of hydrogen is absorbed, the hydrogenationstops. The catalyst is filtered off and the alcohol is removed on thesteam bath, the last traces off in vacuo. The residue is taken up indilute hydrochloric acid and extracted three times with ether to removenonbasic material. The amine, regenerated by the addition of alkali, isextracted with ether. The ether solution of the amine is washed twicewith saturated salt solution, dried over sodium sulfate and thenconcentrated to ca. 50-60 ml. Upon cooling, crystals develop which arefiltered and washed with cold ether to yield3a-hydroxy-20-methylaminopregnan-ll-one, M.P. 136143 C.

A solution of 6.0 g. of 3a-hydroxy-20-methylaminopregnan-l l-one in 300ml. of chloroform is stirred with 300 ml. of 5% sodium hypochloritesolution for one hour. The hypochlorite is removed and the treatmentrepeated. The chloroform layer is separated, washed with water, driedand evaporated to give 3oc-hydroxy-20-(N-methyl-N-chloroarnino)-pregnan-1l-one identical to that in US. Patent No.2,983,736. The 200: and 20,3 isomers are optionally separated byfractional recrystallization from ethanol.

- The above N-chloroamine mixture (6.6 g.) is dissolved in 65 ml. ofredistilled trifluoroacetic acid and irradiated with ultraviolet lightunder nitrogen for 40 minutes. The trifluoroacetic acid is evaporated invacuo to give SOL-hydroxy-l8-chloro-20-methylaminopregnan-1l-one as theester salt. This compound (2.5 g.) in ethanol is added to 5 g. of sodiumethoxide in 50 ml. of ethanol. The mixture is heated at reflux for 10minutes and quenched in water to give 3OL-hydI'0Xy-200t andZO-fl-methylamino- 12,18-cyclopregnan-1 l-one.

Example 2 petroleum ether, then ether. Such trituration inducescrystallization of the desired lS-chloro ester salt, MP. l64-169 C.

A solution of 5 g. ofSlR-hydroxy-l8-chloro-20u-methylaminoallopregnan-ll-one as theO-trifluoroacetoxy trifluoroacetic acid salt in 25 ml. of methanol isadded dropwise with stirring to a hot solution of 10 g. of potassiumhydroxide in 50 ml. of methanol. The mixture is heated at reflux for 5minutes and quenched in 10 volumes of water to give3fi-hydroxy-Zfloc-methylamino-12,18-cycloallopregnan-ll-one, M.P. 228231C., after recrystallization from methanol.

The methanol filtrate and the aqueous filtrate are combined andextracted with methylene chloride. Evaporation of the dried extractsgives a residue which is heated with an excess of acetic anhydride fortwo hours. Quenching in Water and filtration followed by neutralizationof the filtrate and extraction into methylene chloride give 36-acetoxy-conanine-ll-one, MP. l190 C.

The cyclo compound (500 mg.) is heated on the steam bath with an excessof acetic anhydride. Quenching and extraction gives the O,N-diacetylderivative.

Example 3 A mixture of 25 g. of3/8-trifiuoracetoxy48-chloro-20emethylaminoallopregnan-ll-onetrifluoracetate (Example 2), 8 ml. of trifluoracetic anhydride and 625ml. ofdry benzene is heated at reflux for one hour. The cooled solutionis concentrated to an oil which crystallized from methanol to give theamide, Ml. 175-177 C. This compound is dissolved in 300 ml. of ethanolwith 30 ml. of 40% sodium hydroxide solution. After a reflux period ofthree hours, cooling separated a product identical with that of Example2.

Example 4 A mixture of 1 g. of 18-chloro-3u-hydroxy-IGa-methyl-ZO-methylaminopregnan-ll-one (US. Patent No. 2,960,- 503) in a solutionof 2 g. of potassium hydroxide and 20 ml. of methanol is heated for 30minutes and quenched. Working up as in Example 2 gives3u-hydroxy-16amethyl-20-mcthylamino-12,18-cyclopregnan-1 l-one.

Example 5 To 7.2 g. of 5a-hydroxy-6l9-methyl-3,11,20-allopregnantrionein ml. of methanol is added 0.4 g. ofsodium borohydride dissolved inpyridine. After 10 minutes an excess of dilute hydrochloric acid isadded and the mixture extracted with methylene chloride. Evaporation ofthe solvent and chromatography of the residue over alumina yields3,8,5a-dihydroxy-6fi-rnethyl-11,20-allopre nandione.

The dione prepared as above (18.0 g.) and 0.5 g. of platinum oxide areadded to 200 ml. of ethanol containing 10% W./W. of methylamine and themixture hydrogenated until one mole of hydrogen is absorbed. Thecatalyst is removed by filtration and the filtrate evaporated todryness. Treatment of the residue with chloroform-acetic acid thenneutralizing the acid extract gives 35,50; dihydroxy 618 methyl 20o:methylaminoallopragnan-l l-one.

A solution of 7.6 g. of the amine in 500 ml. of anhydrous toluene and100 ml. of cyclohexanone is heated at reflux and a solution of 25.0 g.of aluminum isopropoxide in 100 ml. of toluene is added dropwise withstirring. Refluxing is continued for two hours, 10 ml. of glacial aceticacid is added and the mixture steam distilled. The residue is madebasic, taken into chloroform. The organic extracts are shaken withdilute acid. The acid extracts are made neutral to give 3,1l-diketo-6a-methyI-Z0-rnethylamino-4-pregnene.

A solution of 6.0 g. of 3,1l-diketo-6a-methyl-20-methylarnino-4-pregnene in 300 ml. of chloroform is stirred with 300 ml.of 5% sodium hypochlorite solution for one hour. The hypochlorite isremoved and the treatment repeated. The chloroform layer is separated,washed with water, dried and evaporated to give 3,11- diketo 6oz methyl20 (N methyl N chloroamino)-4-pregnene.

The above N-chlorarnine (6.6 g.) is dissolved in 65 m1. of redistilledtrifluoroacetic acid and irradiated with ultraviolet light undernitrogen for 40 minutes. The trifluoracetic acid is evaporated in vacuoto give crude 18 chloro 3,11 diketo 6m methyl 20methylarnino-4-pregnene.

This 18-chloro compound (2.5 g.) is heated in 3 g. of potassiummethoxide in methanol for two hours. Quenching and working up as inExample 2 gives 3,11- diketo 60c methyl 20 methylamino 12,18 cyclo4-pregnene.

Example 6 A mixture of 750 mg. ofl8-chloro-6B,9a-difluoro-iifihydroxy-ZO-methylaminoallopregnan-1l-one(US. Patent No. 2,959,586), 2 g. of potassium hydroxide and ml. ofmethanol is heated at reflux for one hour, then quenched as in Example 1to give 6,8,9ot-diflll01O-3fi-1IY- droxy--methylamino-l 2, 18-cyclo-allopregnan-l l-one.

Example 7 A mixture of 850 mg. of l8-chloro-6a-fiuoro-3 3-hydroxy-ZO-methylamino-19-norallopregnan-l l-one (US. Patent No.2,959,586), 2.5 g. of sodium hydroxide and 20 ml. of ethanol is heatedat reflux then worked up as in Example 2 to give 6tit-fluoro-33-hydroxy-20-rnethylamino-19nor-12,l8-cycloallopregnan-1 l-one.

Example 8 A mixture of l g. of 18-chloro-9a-fiuoro-3,8-acetoxy-20a-methylamino-allopregnan-1l-one (U.S. Patent No. 2,959,586), 3 g. ofpotassium hydroxide in 40 ml. of methanol is reacted and quenched as inExample 2 to give 90c-flL1OI0-3 fi-hydroxy-20ot-methylamino- 12,18-cyc1oallopregnan-l Lone.

Example 9 A mixture of 750 g. of l8-chloro-20-butylamino-3B-hydroxy-19-norallopregnan-1l-one (prepared as described in U.S. PatentNo. 2,960,503 using ll-keto-ll-norprogesterone), 2 g. of sodiumhydroxide and ml. of methanol is reacted and worked up as in Example 2to give the desired 20-butylamino-3/3-hydroxy-l9-nor-l2,l8-cycloallopregnan-l l-one.

Example 10 To a solution of methylamine in 100 ml. of ethanol (10%w./w.) is added 9.3 g. of 3fi-acetoxy-5-pregnen- 11,20-dione and 0.25 g.of platinum oxide. The mixture is then hydrogenated until one mole ofhydrogen is absorbed. The catalyst is filtered off and the solventevaporated. The residue is taken up in dilute hydrochloric acid, theacid solution made basic and then extracted with chloroform. By removingthe chloroform in vacuo and recrystallization of the residue,3,8-acetoxy- ZOa-methylamino-S-pregnen-ll-one is obtained which ishydrolyzed by refluxing in methanolic potassium hydroxide to the3-hydroxy derivative.

A solution of 5.0 g. of 3B-hydroxy-ZOa-methylamino- S-pregnen-ll-one in250 ml. of toluene and 100 ml. of cyclohexanone is oxidized with 15.0 g.of aluminum isopropoxide by heating at reflux for two hours. Glacialacetic acid (10 ml. in 25 ml. of toluene) is added and the mixture steamdistilled for one hour, then cooled. the mixture is made basic with 40%sodium hydroxide solution, cooled and extracted with chloroform. Theextract is washed with Water, then extracted with 5% acetic acid. Theaqueous extracts are made basic, the solid filtered and recrystallizedfrom acetone to give 3,11- diketo-20u-methylamino-4-pregnene.

A solution of 2.5 g. of the amine in 75 ml. of methylene chloride isreacted with sodium hypochlorite as described to give the N-chloro whichis rearranged to give the 18- chloro by irradiation in trifluoroaceticacid.

The l8-chlor compound (1 g.) is condensed with an excess of ethanolicsodium hydroxide as described above to give 3,11 diketo 20a-methylamino12,18 cyclo-4- pregnene, M.P. 128-130 C.

Example 11 A solution of l g. of3,8-hydroxy-20a-methylaminol2,l8-cycloallopregnan-1l one (Example 2) intetrahydrofuran is added dropwise to a refluxing solution of 0.5 g. oflithium aluminum hydride in 25 ml. of tetrahydrofuran. After refluxingfor 1.5 hours, the reaction mixture is quenched in water and filtered.The filtrate is evaporated and the residue recrystallized from aqueousmethanol to give 3,8,1lB-dihydroxy-ZM-methylamino-l2,18-cycloallopregnane, M.P. 220-240 C.

Example 12 Sodium (0.37 g.) is dissolved in 15 m1. of diethylene glycolwith heating. About 2 m1. of anhydrous hydrazine is distilled into theflask and 1.55 g. of3,8-hydroxy-20amethylamino-lZ,l8-cycloallopregnan-1l-one (Example 2) isadded. After heating at 180 C. overnight, the mixture is distilled untilthe temperature of the reaction mixture is 210 C. and held there for 22hours. The mixture is cooled and diluted with water to separate 35-hydroxy-20a-methylamino-12, l 8-cycloallopregnane, M.P. 192-1945 C. 1

Example 13 A mixture of 5 g. of3,B-hydroxy-Zout-methylaminol2,l8cycloallopregnan-l l-one (Example 2),10 ml. of formic acid and 5 ml. of 40% formaldehyde solution is heatedat reflux for four hours, diluted with water, made basic and filtered.The solid is dissolved in hot ethanol. The alcoholic solution is madebasic with 10% sodium hydroxide, then diluted with water and cooled.Recrystallization of the resulting solid from ethanol gives 3,8hydroxy-ZOa-dimefhylamino-12,l8-cycloallopregnanll-one, M.P. l8l-l84 C.Acetylation with an excess of acetic anhydride on the steam bath, thenquenching gives the acetate derivative.

Using this procedure on 20-butylamino-3fl-hydroxy-19-nor-12,18-cycloallopregnan-ll-one (1 g.), gives the 20-methylbutylamino compound.

Example 14 A mixture of 4 g. of the ZOa-dimethyIamin-o compound ofExample 13, 10 ml. of methyl iodide and ml. of benzene is heated atreflux for five hours. The cooled mixture is diluted with ether toseparate the methiodide quaternary salt, M.P. 240 C.

The 20 methylbutyl compound is similarly reacted with ethyl chloride toform the ethochloride quaternary salt.

Example 15 A mixture of 1 g. of the methiodide salt of Example 14, 0.5g. of sodium methoxide and 10 ml. of dimethylformamide is heated atreflux for 10 minutes, then on the steam bath for 30 minutes. The cooledmixture is poured into Water and extracted with ether to give3fl-hydroxy-l lketo-lZ,18-cyclo-20-allopregnene, disclosed and claimedin copending application, Serial No. 81,705 filed January 10, 1961.

What is claimed is:

l. A chemical compound selected from the group consisting of a base, itsacid addition and its quaternary ammonium salts, the base having thestructural formula:

in which R is a member selected from the group con-.

sisting of hydroxy and keto; R and R are members selected from the groupconsisting of hydrogen and methyl; R is a member selected from the groupconsisting of hydrogen, hydroxy and keto; R is a member selected fromthe group consisting of hydrogen and fiuoro; R is a member selected fromthe group consisting of hydrogen, methyl and fluoro; R and R are membersselected from the group consisting of hydrogen and lower alkyl havingfrom one to four carbon atoms, at least one of which is lower alkyl; andY is a member selected from the group consisting of ethylene andvinylene.

2. 3B hydroxy-20u-methylamino-12,l8 cycloallopregnan-ll-one.

3. 3a-hydroxy-ZO-methylamino-12, l 8-cyclopregnan-l 1- one.

4. 3,8 hydroxy 20a methylarnino 12,18 cycloallopregnane.

5. 3 8,111.! dihydroxy 20oz methylamino 12,18- cycloallopregnane.

6. 3,11 diketo 20a methylamino 12,18 cyclo 4- pregnene.

7. 35 hydroxy 20 loweralkylamino 19 nor 12, 18-cycloallopregnan-ll-one.

8. 3e hydroxy 20a dimethylamino 12,18 cycloallopregnan-l l-one.

9. The process of preparing a compound having the formula:

8 in which R is a member selected from the group consisting of hydroxyand keto; R and R are members selected from the group consisting ofhydrogen and methyl; R is a member selected from the group consisting ofhydrogen and fluoro; R is a member of the group consisting of hydrogen,methyl and fiuoro; R and R are members selected from the groupconsisting of hydrogen and lower alkyl having from one to four carbonatoms, at least one of which is lower alkyl; and Y is a member selectedfrom the group consisting of ethylene and vinylene, comprising reactingin an alcoholic solution of a base selected from the group consisting ofan alkali metal hydroxide, methoxide and ethoxide at temperatures fromabout room temperature up to the reflux temperature of the reactionmixture an 18-halo compound selected from the group consisting of a baseand its acid addition salts, the base having the formula:

in which R is a member selected from the group consisting of hydroxy,alkanoyloxy having a maximum of 6 carbon atoms, trifluoroacetoxy andketo; R and R are members selected from the group consisting of hydrogenand methyl; R is a member selected from the group consisting of hydrogenand fluoro; R is a member selected from the group consisting ofhydrogen, fluoro and methyl; R and R are members selected from the groupconsisting of hydrogen and lower alkyl having from one to four carconatoms, at least one of which is lower alkyl; Y is a member selected fromthe group consisting of ethylene and vinylene; and X is a memberselected from the group consisting of chloro and bromo.

10. The process of claim 9 characterized in that the base is potassiumhydroxide.

11. The process of claim 9 characterized in that the base is sodiumhydroxide.

12. The process of claim 9 characterized in that the 18-halo compound isSB-triiluoroacetoxy-18-chloro-20otmethylaminoallopregnan-ll-onetrifluoroacetate salt.

No references cited.

1. A CHEMICAL COMPOUND SELECTED FROMTHE GROUP CONSISTING OF A BASE, ITSACID ADDIRION AND ITS QUATERNARY AMMONIUM SALTS, THE BASE HAVING THESTRUCTURAL FORMULA: